Prof Dr Sergülen Dervişoğlu

AmyloidosisCalcification andstones

Amyloidosis

Pathologic proteinaceous substanceDeposited between cellsWide variety of clinical settingsInsidious depositionImmunological mechanism is probablyresponsible

Amyloidosis

Standart tissue stainsAmorphousEosinophilicHyaline extracellular substanceProgressive accumulationPressure on adjacent cell---atrophy

Amyloidosis

Differentiate from other hyaline pinkdepositsCollagen, fibrinMethyl violet--- metachromatic stainingreaction---deep purpleCongo red --- orange redPolarized microscopy--- greenbirefringance

Amyloidosis

Not chemically distinctSeveral different pathogenetic mechanismNot be considered as a single diseaseThree major and several minor biochemicalforms

Physical nature

Non branching fibril proteins95%P componentGlycoproteinNonproteineous substances derived fromconnective tissue in which amyloiddeposited

Chemical nature

Amyloid proteinsAL--- amyloid light chain---derived from plasmacellsAA---amyloid associated---nonimmunoglobulinprotein synthesized by liverDistinct clinicopathologic settingsAbeta---amyloid found in cerebral lesions of Alzheimer patients

Amyloidosis

AL type--- immunoglobulin secreting cellsMonoclonal B cell proliferationAA type--- secondary amyloidosisTransthyretin (TTR) mutant form---familial amyloid polyneuropathiesBeta 2 microglobulin---longtermhemodialysisBeta amyloid protein---Alzheimer disease

Amyloid clasification

Based on its constituent chemical fibrilsAA, AL, ATTRIt can be both systemic or localizedClinically---Primary—Immunocytedyscrasias---Monoclonal gammopathySecondary---AA---reactive systemicamyloidosis---underlying chronic disease

Systemic generalized primaryamyloidosis

Immunocyte dyscrasiasSystemicAL typePlasma cell dyscrasiasMultiple myelomaMonoclonal gammopathyAbnormal protein

Systemic generalized secondaryamyloidosis

Underlyig chronic disease---AA typeReactiveTbc, Ulcerative colitis,Chr. OMBronchiectasisRA, AS, İnflammatory bowel diseaseHodgkin diseaseRenal cell carcinoma

Hereditary familial systemicamyloidosis

Familial, rareGeographic limitationFMF---AA proteinsReccurent bouts of inflammationFamilial amyloiditic polyneuropathyMutant transthyretin

Localized amyloidosis

Single organ, tissueNodular massesTumor forming amyloid accumulationLung, larynx, skin, urinary bladder, tongue, eyeAL typePeripheral plasmacytes

Endocrine amyloid

Microscopic deposits of localized amyloidEndocrine tumorsMedullary carcinoma of thyroidIslet cell tumor of pancreasPheochromocytomaUnique proteinsPolypeptide hormones

Hemodialysis associatedamyloidosis

Longterm hemodialysis for renal failureDeposition of beta2 microglobulineCan not be filtered through dialysismembranesAmyloid deposition in the synovium,joints, tendon sheath60-80% of patients

Senile amyloidosis---Amyloid of aging

Elderly patients ( 70-80)Dominant involvement in the heartDysfunctionSenile cardiac amyloidosisRestrictive cardiomyopathyArrhythmiasNormal or mutant form of transthyretinSystemic—lungs, pancreas, spleen

Pathogenesis

Stimulus----soluble precursor---Insoluble fibersUnknown ( Carcinogen?)---Monoclonal B cellproliferation---plasma cells---Ig Light chain---limited proteolysis---P component---AL amyloidChronic inflammation---Macrophage activation---IL1,6 secretion---Liver cells---SAA---Limitedproteolysis---P component--- AA amyloidGenetically determined alteration---abnormalTTR---ATTR amyloid

Organ findings in amyloidosis

No distinct or consistent pattern of distributionSecondary form tend to be severe systemic involvement---kidneys, liver, spleen, lymph nodes, adrenal glands, thyroidImmunocyte associated---heart,kidney,gastrointestinal tract, peripheral nerves,skin, tongue

Macroscopic apperarance

Enlarged, firmWaxy appearanceSufficiently large deposit---iodinepainting of cut surface---yellow colorturns to blue violet—after application of sulfuric acid

Microscopy

Staining with specific dyesCongo redCresyl violetElectron microscopic confirmationPolarized microscopySpecific immunohistochemistry forsubtypes AA, AL, ATTR

Kidney amyloidosis

Most commonMost seriousRenal amyloidosis is the major cause of deathNormal in size and color or enlargedIn advanced case shrunken/contracted---vascular narrowing---due to depositionof amyloid in arteriolar wall

Kidney amyloidosis microscopy

Glomerular accumulation/ Mesangial matrixInterstitial peritubular tissueArteries, arteriolesWidening of glomreular capillaries basalmembraneDistortion of vascular tuftGlomeruli turn into confluent masses of amyloid

Amyloidosis of the spleen

Splenomegaly moderate to markedTwo patterns of depositionDeposition limited to splenic follicles—white pulp---tapioca like granules---SAGO spleenAmyloid depoistion in sinusoidal walls andconnective tissue framework---red pulp---maplike---LARDECEOUS spleen

Amyloidosis of liver

Moderate to marked hepatomegalyAmyloid deposition in Disse spaceProgressive pressure atrophy of adjacenthepatocyteTotal replacement of liver parenchymaVascular involvement, Kupffer celldepositionNormal liver function is usually preserved

Amyloidosis of heart

Enlarged, firmNo significant macroscopic changeFocal subendocardial accumulationBetween muscle fibersConduction system may be damagedPressure atrophy of fibersIntractable heart failure

Amyloidosis of other organs

Adrenals, pitutary glands, thyroidAdrenals first site is zona glomerulosaReplacement of parenchymaGIS---early lesions blood vessel walls—BxdiagNodular deposition in the tongueRespiratory tractAlzheimer---brain

Clinical correlation

No clinical findingsIt may cause deathMagnitude of depositsParticular organ or sites affectedNonspesific general symptomsWeight loss, weakness,syncope

Clinical findings of amyloidosis

Renal involvement---proteinuriaNephrotic syndromeRenal failure---uremiaCardiac amyloidosis---insidious congestiveheart failureConduction disturbancesGastrointestinal amyloidosis---asymptomatic---malabsorption, diarrhea

Prognosis

Generalized amyloidosis poor prognosisImmunocyte derived form---2 yearsmedian survivalMyeloma associate ones---poorerprognosisDepends on the control of underlyingcause

Pathologic calcification

Abnormal deposition of calcium saltsTogether with small amounts of othermineral saltsCa phosphateCa carbonateOther salts

Calcification

Dystrophic calcificationNonviable/dying tissueMetastatic calcificationVital tissues

Dystrophic calcification

Areas of necrosisCoagulative, liquefactive typeEnzymatic fat necrosisWhenever the necrotic tissue persist forlong period of time

Dystrophic calcification

Not dependent on an increase in thecalcium content of the bloodInfluenced by local relative alkalinity of the damaged tissueAbnormal amount of phosphateaccumulating in necrotic tissue may favorthe deposition of Ca salts

Dystrophic calcification

Atheroma plaques in advancedatherosclerosisAging or damaged heart valvesCalcific aortic stenosisDead fetus intrauterinLithopedion

Macroscopy

Fine, white granulesClumpsGritty depositsStone like appearance in lymph nodes ( Tbc)In fat necrosis---Ca and released fattyacids---SOAPS

Microscopy

Hematoxylen/eosin stains---basophilic, amorphous, granular, clumpedIntracellularExtracellularBoth locationIn the course of time---heterotopic bone formation in the focus of calcification

Single necrotic cell

Progressive acquesition of outer layers bymineral depositsLamellated configurationPsammoma bodiesResemblance to grains od sand---Psammom=sand---Greek word

Psammoma bodies

Papillary carcinoma of thyroidPapillary carcinoma of ovaryMeningiomaIn asbestosis---calcium iron salts---longslender spicules---exotic dumbbell forms

Pathogenesis

Formation of crystalline calcium phosphatemineral---apatite form ( resemblinghydroxyapatite of bone)InitiationPropagationIntracellular calcification---in the mitochondriaof dead or dying cellExtracellular calcification---phospholipids in membrane bound vesicles

Metastatic calcification

Calcification in previously undamagedtissueInterstitial tissue of blood vesselsKidneysLungsGastric mucosaMorphology is similar with dystrophiccalcification

Hypercalcemia

HyperparathyroidismVit D intoxicationSystemic sarcoidosisMilk-alkali syndromeHyperthyroidismIdiopathic hypercalcemia of infancyAddison’s disaeseIncreased bone catabolism

No clinical dysfunctionMassive involvement of lungs---X-ray changes-respiratory difficultiesIn the kidney---nephrocalcinosis---in time---renal damage

Increased bone catabolism

Disseminated bone tumorsMultiple myelomaMetastatic cancer leukemia

Pathologic ossification

Preceeded by calcificationTransformed fibroblasts---osteoblastsHeterotopic bone formationBone marrowReactive, metaplasticMyozitis ossificans---localized aftertrauma to a muscle

Stones or calculi

In urinary tract---by precipitation of chemicalsalts in urineInfectionStasisIncreased urinary concentration of crystalloidsChanges of a physical and chemical nature of urine or urinary tract that favor theprecipitation

Types of urinary tract stones

White stones---mixtures of uric acid, Caoxalate and phosphatesCertain constituents predominateUric acid and cystine---precipitate in an acid urinePhosphate---associated with alkaline urinesOxalate stones---any pH

Renal calculi

Obstruction of outflow of urineStasis---Promote infectionPyelonephritisRenal colic painDilatation of ureter or renal pelvisHydroneprosis

Gall stones

Normal constituents of bileCholesterolCalcium biluribinateCalcium carbonateMain substances

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Pure gallstones

Excess of the stone forming substance in bileDisturbance of liver function ormetabolismCholesterol stone mostlyPigment stones ( Ca biluribinate)

Mixed gallstones

Most common form ( 80%)Exact mechanism of their formation is uncertainMultipleHuge numbers

Combined gall stones

Solitary stoneCholesterol nucleusOuter shell similar to a mixed gallstone

References and further reading

Robbins Pathologic Basis of Disease, Cotran, Kumar 2004Pathology Illustrated, Macfarlane, Reid,Callande 2000Sandritters Color Atlas and Textbook of Macropathology, Thomas, Kirstn, 1984Basic Pathology, 6th ed, Kumar, Kotran, RobbinsPathology Rubin, Farber, 1999Mohan Harsh Textbook of Pathology, 2005Cerrahpaşa Pathology archievesInternet (various medical web sites)